Browsing by Author "Andjus, P. R."

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    A change in the pattern of activity affects the developmental regression of the Purkinje cell polyinnervation by climbing fibers in the rat cerebellum
    (Elsevier, 2003-10-15) Andjus, P. R.; Zhu, Lan; Cesa, R.; Carulli, D.; Strata, Piergiorgio
    Pattern of activity during development is important for the refinement of the final architecture of the brain. In the cerebellar cortex, the regression from multiple to single climbing fiber innervation of the Purkinje cell occurs during development between postnatal days (P) 5 and 15. However, the regression is hampered by altering in various ways the morpho-functional integrity of the parallel fiber input. In rats we disrupted the normal activity pattern of the climbing fiber, the terminal arbor of the inferior olive neurons, by administering harmaline for 4 days from P9 to P12. At all studied ages (P15-87) after harmaline treatment multiple (double only) climbing fiber EPSC-steps persist in 28% of cells as compared with none in the control. The ratio between the amplitudes of the larger and the smaller climbing fiber-evoked EPSC increases in parallel with the decline of the polyinnervation factor, indicating a gradual enlargement of the synaptic contribution of the winning climbing fiber synapse at the expense of the losing one. Harmaline treatment had no later effects on the climbing fiber EPSC kinetics and I/V relation in Purkinje cells (P15-36). However, there was a rise in the paired-pulse depression indicating a potentiation of the presynaptic mechanisms. In the same period, after harmaline treatment, parallel fiber-Purkinje cell electrophysiology was unaffected. The distribution of parallel fiber synaptic boutons was also not changed. Thus, a change in the pattern of activity during a narrow developmental period may affect climbing fiber-Purkinje cell synapse competition resulting in occurrence of multiple innervation at least up to 3 months of age. Our results extend the current view on the role of the pattern of activity in the refinement of neuronal connections during development. They suggest that many similar results obtained by different gene or receptor manipulations might be simply the consequence of disrupting the pattern of activity.
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    Metabotropic glutamate receptor-mediated currents at the climbing fiber to Purkinje cell synapse
    (ACS Publications, 2005-11-28) Andjus, P. R.; Bajic, A.; Zhu, Lan; Schachner, M.; Strata, Piergiorgio
    Different forms of synaptic plasticity in the cerebellum expressed at the synapses onto Purkinje cells (PCs) are mediated by membrane metabotropic glutamate receptors (mGluRs). There are three main mGluR groups with a total of 8 subtypes. Although mGluRs are also found at the climbing fiber (CF) to PC synapses, the distribution and biological activity of their types is not well-known. Using whole cell patch-clamp recordings from PCs in rat cerebellar slices with inhibitors of ionotropic receptors and glutamate uptake blockers we demonstrate a complex pharmacology of currents obtained by CF stimulation. The mGluR1 specific antagonist CPCCOEt in a group of cells suppressed this response, but in a similar number of other cells it induced a potentiating effect. It was found that a switch between these two biopharmaceutical effects might occur with age.
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    Pharmacology of the metabotropic GluR-mediated current at the climbing fiber to Purkinje cell synapse
    (Taylor and Francis, 2003-10-02) Zhu, Lan; Strata, Piergiorgio; Andjus, P. R.
    Different forms of synaptic plasticity in the cerebellum are mediated by metabotropic glutamate receptors (mGluRs). At parallel fiber (PF) to Purkinje cell (PC) synapses activation of mGluR gives rise to a well known slow synaptic current inhibited by antagonists ofmGluR1. The distribution of mGluR types in the climbing fiber (CF) to PC synapses is not well known. Only recently an mGluR1-mediated all-or-none post-synaptic current was also demonstrated at the CF-PC synapse (Dzubay & Otis, Neuron 2002; 36: 1159). Using whole cell patch-clamp recordings from PCs in rat cerebellar slices with AMPA receptors blocked(NBQX, 10 or CNQX, 20mM) and impaired glutamate uptake (TBOA, 100 mM) we demonstrate a more complex pharmacology of a current obtained by single or train (10 or 100 Hz) CF stimulation. The mGluR1 specific antagonist CPCCOEt, 100 mM in a group of cells suppressed this response while in a similar number of other cells it induced a potentiating effect. The antagonists of mGluR groups II and III (LY341495 and MSOP, respectively) predominantly suppressed the current. In addition, 100 mM MSOP did not occlude the inhibition by 0.2 mM LY341495. The ambiguous effect of CPCCOEt was checked by measuring the paired-pulse depression of the CF EPSC, which was not changed with the antagonist. The paired-pulse plasticity was also not changed by CPCCOEt in low (0.5mM) external Ca2+ (used to prevent saturation of AMPARs), thus excluding a presynaptic effect. However, CPCCOEt induced arise in the amplitude (by 25%) as well as a prolongation of the decay time of CF EPSCs at normal 2mM Ca2+, i.e. under conditions of AMPAR saturation (11.7 ± 0.7 ms vs. 15.8 ± 1.5 ms), thus indicating an effect of postsynaptic origin. In 0.5 mM Ca2+ the decay of CF EPSCs was faster (7.5 ± 1.2 ms) but it was also prolonged by CPCCOEt (8.8 ± 1.2 ms). However, the CF EPSC amplitude was not significantly affected indicating an underlying Ca2 2+-dependent mechanism. Thus, the pharmacology of the PC mGluR-mediated response points to a dual postsynaptic role of mGluR1 giving rise to a slow postsynaptic current but also regulating other presumably mGluR-dependent currents via second messenger molecules and Ca2 i. The additional electrophysiological role of mGluR II & III types was also indicated. Such a complex regulatory mechanism may have an important role in them GluR-dependent forms of homosynaptic plasticity and motor learning at the CF-PC synapse.
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    Pharmacology of the metabotropic glutamate receptor mediated current at the climbing fiber to Purkinje cell synapse.
    (Elsevier, 2005) Zhu, Lan; Strata, Piergiorgio; Andjus, P. R.
    Different forms of synaptic plasticity in the cerebellum are mediated by metabotropic glutamate receptors (mGluRs). At parallel fiber (PF) to Purkinje cell (PC) synapses activation of mGluR gives rise to a well known slow synaptic current inhibited by antagonists of mGluR1. The distribution of mGluR types in the climbing fiber (CF) to PC synapses is not well known. However, a mGluR1alpha-mediated all-or-none postsynaptic current was also demonstrated at the CF-PC synapse (Dzubay and Otis, Neuron 36, 1159, 2002). Using whole cell patch-clamp recording from PCs in rat cerebellar slices with AMPA receptors blocked and glutamate uptake impaired we demonstrate a more complex pharmacology of a current obtained by single or train CF stimulation. The mGluR1 specific antagonist CPCCOEt in a group of cells suppressed this response while in a similar number of other cells it induced a potentiating effect. The antagonists of mGluR groups II and III (LY341495 and MSOP, respectively) predominantly suppressed the current. The ambiguous effect of CPCCOEt was checked by measuring the paired-pulse depression of the CF EPSC, which was not changed with the antagonist in normal as well as in low (0.5 mM) external Ca(2+) (used to prevent saturation of AMPARs), thus excluding a presynaptic effect. However, CPCCOEt induced a rise in the amplitude (by approximately 50%) as well as a prolongation (p<0.05) of the decay time of CF EPSCs at normal 2 mM Ca(2+), i.e. under conditions of AMPAR saturation, thus indicating an effect of postsynaptic origin. In 0.5 mM Ca(2+) the decay of CF EPSCs was longer but it was also significantly prolonged (p?0.01) by CPCCOEt. However, the CF EPSC amplitude was not significantly affected indicating an underlying Ca(2+)-dependent mechanism. Thus, the pharmacology of the PC mGluR-mediated response points to a dual postsynaptic role of mGluR1 giving rise to a slow postsynaptic current but also regulating other presumably mGluR-dependent currents via second messenger molecules and Ca(2+). The additional electrophysiological role of mGluR II & III types was also indicated. Such a complex regulatory mechanism may have an important role in the mGluR-dependent forms of homosynaptic plasticity and motor learning at the CF-PC synapse.
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    Short-term facilitation and depression in the cerebellum: some observations on wild-type and mutant rodents deficient in the extracellular matrix molecule tenascin C
    (Annals of the New York Academy of Sciences, 2005-09-12) Andjus, P. R.; Bajic, A.; Zhu, Lan; Schachner, M.; Strata, Piergiorgio
    Short-term plasticity was studied on synapses to Purkinje cells (PC): paired-pulse facilitation in parallel fibers (PF) and paired-pulse depression in climbing fibers (CF). Both phenomena relate to synaptic strength. These forms of short-term plasticity were tested on cerebellar slices in rat by early postnatal synchronous stimulation of olivary neurons (i.e., CFs) with harmaline and by inhibition of a metabotropic glutamate receptor (mGluR) as well as in mice that were deficient in the extracellular matrix glycoprotein tenascin-C. Harmaline stimulation delayed the developmental competition between CF inputs and maintained multiple innervation. Paired-pulse depression of the CF-PC synapse after harmaline treatment was more expressed. However, paired-pulse facilitation in PF-PC synapses remained unchanged. Electrophysiological responses of postsynaptic mGluR1 in CF-PC synapses could be obtained only with AMPA receptors blocked and glutamate uptake impaired. The mGluR1-specific antagonist CPCCOEt suppressed the CF-mGluR EPSC in some PCs and potentiated it in other PCs. CF paired-pulse depression was not changed with CPCCOEt, thus excluding a presynaptic effect. The postsynaptic effect was underlined by CPCCOEt-induced rise in amplitude of EPSC and by a prolongation of its decay time. Tenascins are extracellular matrix glycoproteins that may restrict the regenerative capacity of the nervous tissue. Testing short-term presynaptic plasticity in tenascin-C-deficient mice showed that CF paired-pulse depression was less expressed while PF paired-pulse facilitation was augmented except in a group of cells where there was even depression. The results underline differences in forms of short-term plasticity with regard to susceptibility to diverse modulatory factors.